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................................................................................................................ slightly, increased frequency of muscle symptoms in statinallocated groups.239,240 The Anglo-Scandinavian Cardiac Outcomes Trial  Lipid-Lowering Arm (ASCOT-LLA) study addressed this issue by comparing the incidence of four different adverse events, including muscle-related symptoms, during both the blinded, placebo-controlled trial and its open-label extension study.238 They concluded that a nocebo effect (i.e. one caused by negative expectations) may partly explain the higher frequency of SAMS in observational studies compared with in trials. Suggested practical management of muscular symptoms is shown in Supplementary Figure 6.198,234,241 Several studies have shown a considerable LDL-C-lowering effect of alternative dosing, such as every other day or twice a week, with atorvastatin or rosuvastatin.242 Although no clinical endpoint trials are available, this strategy should be considered in high-risk patients in whom statin treatment with daily doses is not possible.

8.1.4.2 Adverse effects on the liver. The activity of alanine aminotransferase (ALT) in plasma is commonly used to assess hepatocellular damage. Mild elevation of ALT occurs in 0.52.0% of patients on statin treatment, more commonly with potent statins or high doses. The common definition of clinically relevant ALT elevation has been an increase of three times the ULN on two consecutive occasions. Mild elevation of ALT has not been shown to be associated with true hepatotoxicity or changes in liver function. Progression to liver failure is exceedingly rare, therefore routine monitoring of ALT during statin treatment is no longer recommended.243 Patients with mild ALT elevation due to steatosis have been studied during statin treatment and there is no indication that statins cause any worsening of liver disease.244246

8.1.4.3 Increased risk of new-onset diabetes mellitus. Patients on statin treatment have been shown to exhibit an increased risk of dysglycaemia and development of type 2 diabetes mellitus (T2DM). Several studies have shown that this is a consistent, dose-related effect.232 A minor, not clinically relevant elevation of glycated haemoglobin (HbA1c) has also been observed. The number needed to cause one case of diabetes has been estimated as 255 over 4 years of statin treatment.247 However, the risk is higher with the more potent statins at high doses,248 and is also higher in the elderly, and in the presence of other risk factors for diabetes such as overweight or insulin resistance.249 Overall, the absolute reduction in the risk of CVD in high-risk patients clearly outweighs the possible adverse effects of a small increase in the incidence of diabetes.233 This effect is probably related to the mechanism of action of statins, as Mendelian randomization studies have confirmed the increased risk of DM in individuals with HMG-CoA reductase polymorphisms that reduce cholesterol synthesis.250

8.1.4.4 Increased risk of haemorrhagic stroke. In observational studies, TC is negatively associated with haemorrhagic stroke, and in the CTT meta-analysis, there was a 21% [95% confidence interval (CI) 541%; P=0.01] relative increase per mmol/L lower LDL cholesterol in haemorrhagic stroke.34,251,252 However, other meta-analyses have yielded conflicting findings and there is a need for further exploration of the risk of haemorrhagic stroke in particular types of patients. Note, however, that the overall benefit on other stroke subtypes greatly outweighs this small (and uncertain) hazard.34,36

8.1.4.5 Adverse effects on kidney function. There is no clear evidence that statins have a clinically significant beneficial or adverse effect on renal function.253 An increased frequency of proteinuria has been reported for all statins, but has been analysed in more detail for rosuvastatin. With a dose of 80 mg, a frequency of 12% was reported. With the approved doses of <40 mg, the frequency is much lower and in line with the frequency for other statins. The proteinuria induced by statins is of tubular origin, usually transitory, and is believed to be due to reduced tubular reabsorption and not to glomerular dysfunction.254,255 In clinical trials, the frequency of proteinuria is generally low and, in most cases, is not higher than for placebo.256

8.1.4.6 Interactions. A number of important drug interactions with statins have been described that may increase the risk of adverse effects. Inhibitors and inducers of enzymatic pathways involved in statin metabolism are summarized in Table 10. All currently available statins—except pravastatin, rosuvastatin, and pitavastatin—undergo major hepatic metabolism via the CYPs. These isoenzymes are mainly expressed in the liver and intestine. Pravastatin does not undergo metabolism through the CYP system, but is metabolized by sulfation and conjugation. CYP3A4 isoenzymes are the most abundant, but other isoenzymes such as CYP2C8, CYP2C9, CYP2C19, and CYP2D6 are frequently involved in the metabolism of statins. Thus, other pharmacological substrates of these CYPs may interfere with statin metabolism. Conversely, statin therapy may interfere with the catabolism of other drugs that are metabolized by the same enzymatic system. Combination of statins with gemfibrozil enhances the risk of myopathy, and its association with statins must be avoided. There is no or very little increased risk for myopathy when combining statins with other fibrates, such as fenofibrate, bezafibrate, or ciprofibrate.259,260

Table 10 Drugs potentially interacting with statins metabolized by cytochrome P450 3A4 leading to increased risk of myopathy and rhabdomyolysis

Anti-infective agents Calcium antagonists Other Itraconazole Verapamil Ciclosporin Ketoconazole Diltiazem Danazol Posaconazole Amlodipine Amiodarone Erythromycin Ranolazine Clarithromycin Grapefruit juice Telithromycin Nefazodone HIV protease inhibitors Gemfibrozil Adapted from Egan and Colman,257 and Wiklund et al.258 HIV = human immunodeficiency virus. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026